5,6-substituted dihydropyrimidines



US. Cl 260-260 2 Claims ABSTRACT or THE DISCLOSURE5-bromo-5-nitro-6-lower alkoxy hydrouracils and 5- bromo 5trifiuoromethyl-o-lower hydroxy hydrouracils are prepared inter alia bytreating S-nitrouracil or 5-(ot,oc, a-trifluoromethyDuracil with a loweralkyl ester of hydrobromic acid. The compounds are useful asanti-bacterial/ anti-fungal agentst g This invention relates to5,6-substituted dihydropyrimidines More particularly, the inventionrelates to novel pyrimidines of the formula wherein X is nitro ortrifiuoromethyl and R is lower alkyl,

The term lower alkyl as used herein represents a straight or branchedchain hydrocarbon containing from. 1 to 7 carbon atoms such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl and the like,

The compounds of this invention can be prepared conveniently by any oneof several alternatives. For example, they can be prepared by reactingthe starting base, i.e., S-nitrouracil or5-(a,u,a-trifluoromethyl)uracil, with a lower alkyl ester of hypobromicacid, Alternatively, such compounds can be prepared by reacting thestarting base with bromine and a suitable monohydric alcohol, ire, amonohydric lower alkanol, In the first method, one can use, for example,ethyl hypobromite or butyl hypobromite, etci, as the hypobromic acidalkyl ester reactant.

In the second method there is employed bromine and a lower alkylmonohydric alcohol having a chain length of from 1 to 7 carbon atoms asthe alcohol reactantq Lower alkanols which are well suited for use inthis method are, for example, methanol, ethanol, propanol, isopropanol,butanol, isobutanol, etc The reaction with bromine or alkanol can beconveniently carried out by treating with bromine a suspension of theappropriate base in the desired lower alkanol, preferably in the presence of an acid binding agent such as potassium car bonate, sodiumcarbonate, silver carbonate, etc, which will bind the free hydrogenbromide formed in the re action. The reaction temperature employed ineither of the preparative methods described above is not critical andeither reaction, i.e,, the reaction with the lower alkyl ester ofhypobromic acid or the reaction with bromine and a lower alkanol, can beconveniently carried out at room temperature though higher or lowertemperatures, preferably a temperature within the range of about 0 toabout 100 C,, are suitably employed,

The novel compounds of this invention, let, the com= pounds of FormulaI, are useful as germicidal agents and anti-fungal agents being active,for example, against a variety of bacteria, yeasts, mold and fungi, Morepartic= ularly, the novel compounds of this invention have been shown topossess broad spectrum anti-bacterial. and anti cause REFERENCE MPatented Maro 24, 1970 fungal activity. They are active against a widevariety of Bram-positive and Gram-negative bacteria, fungi, protozoa,molds and yeast. For example, they can be used to inhibit the growth ofbacteria such as Staphylococcus aureus, Streptococcus hemo'lyticus,Pseudomonas aeruginOsa, Proteus vulgaris, Bacillus simplex, etc. Thecompound 5-bromo-5-nitro-6-methoxyhydrouracil has been. found to'possess an especially broad spectrum anti-microbial activity, possessinga high degree of activity against, among others, the followingorganisms: Escherichia coli, Diplococcus pneumoniae, Salmonella thypi,Staphylococcus aureus, Streptococcus hemolyticus, Pseudomonasaeruginosa, Proteus vulgaris, Candida albicans, Microsporum audouini, Trichophyton mentagrophytes, T richomonas vaginalis, Endamoebahistolytica, Asper-= gillus niger, Aspergillus oryzae, Bacillus simplex,Actinomyces cellulosae, Paecilomyces varioti and Saccharomycescerevisiae,

In View of their broad spectrum anti-microbial activities, the novelcompounds of this invention are particularly well suited for such usesas contact disinfectants or as additives for the preservation ofmaterials subject to microbial deterioration such as, for example,various medicaments, paints, powders, varnishes, plastics, furs,leather, cutting oils, ointments, cosmetics, etc, They can also be usedas the active ingredients of various topical anti-microbial compositionsuseful in the treatment of microbial diseases.

As indicated the novel compounds of this invention can be effectivelyused in preventing or arresting the growth of microorganisms byapplication to the microorganism habitat. The compounds can be suitablyemployed in solution either in water or in an organic solvent in bothaqueous and nonaqueous suspensions such as lotions, ointments, creams orpastes or in suspension or solution in a paint, varnish or oil, etc. Thecompounds can also be used in dry form in a dusting powder or in anyother way that antiseptics and preservatives are generally employed, Thepredominant process employing the compounds as antiseptics, however, isone involving aqueous systems such as, for example, when the compoundsare employed in aqueous emulsions to preserve machine cutting oils andthe like,

This invention 'will be more fully understood from the specific exampleswhich follow,

EXAMPLE 1 Preparation of S-bromo-S-nitro-6-methoxyhydrouracilS-nitrouracil, 314g, (0.2 mole), suspended in methanol, 3 1., andbromine, .32 g., 0.4 mole, 10 ml., were stirred for 15 minutes, A slurryof silver carbonate, 30 g. in methanol, was added and stirring wascontinued for 12 hours, After filtering from the silver salts thesolution was evaporated in vacuo and the residue recrystallized fromwater or ethyl acetate ligroin. The compound melted at 200203 withdecomposition. The decomposition products were predominatelyS-nitrouracil and decomposition products of methyl hypobromite,

EXAMPLE 2 Preparation of S-bromo-S-nitro-6 ethoxyhydrouraci1 Prepared inanalogy to Example 1 by substituting the methanol with ethanol. Theproduct was recrystallized from ethyl acetate-ligroin, Melting point,200202 with decomposition,

EXAMPLE 3 Preparation of S-bromo-S-trifluoromethyl-G- methoxyhydrouracilA solution of methyl hypobromite was prepared by the addition of 5,5 g.(20 mmoles) of silver carbonate to a so- 3 4 4t lution of 1.6 g. (10mmoies) of bromine in '20 m1. of methgs anol which, had been cooled to---t t the resulting Perform suspension was stirred. at l0 (1. for 3G:rninmtes than 'ljween 0 Mi MW. o filtered rapidly into solution of 0.77t f4 ftil'l'iiJlfiS) of 5 Atlas (34.706 beeswax derivative 2 .-i 2

trifiuoromethyluracil it ml: of httlliil. previously E '3' AtlaPolyosyetlrylene splfjnita'n monogatrnitn're. cooled in an ice bath.After 1 hr in the ice hath exami olyost e nv ene snvbit-n neeswaxderivative.

nation of the reaction mixture by ultraviolet spectro {B} photometry inmethanol showed. maximum. in the 11L Surbm 5 V H p Mr W A I? travioletspectrum at. wavelengths greater than 240 m W 2; 42 The somewhat opaquesolution was filtered twice 10 Q y through Celite for clarification. andthe filtrate evaporated Y r t ",i i f" 1 elit '1 (Att to dryness invacuo. After trituratioo W ether; the white u solid. was removed byfiltration. and tied. with ethet' n; and. petroleum ether. The crude...II fifz-5-iflfi'fl0f0 Pg fumg methyl-6-methoxyhydrouracil thusisolated melted at 239- 240 with gas evolution Recrystallization from 6ml of n-butyl-acetate gave pure i hromo -trifluoromethyl-6- Theingredients in Part A were put into a suitable glass lined kettle andwere heated to 70 C, The ingredients in 1 0 Z 2" CL in a separatekettleq Part methox h drouracil meltin at. 246448 (.0 PM B Wm healed m yy g B was then. added to Part A with agltation. Perfume was Ngtte:274In, 575500 heated at C. and material was poured into jars.

i What is claimed is:

EXAMPLE 4 L A compound of the formula ihromo-i-nitro-ti-methm yhvdr: mfatal". Uzi paint formulatiom An. oil. q i my N 0R H Iron Oxide p st 2;The compound according to claim 1 wherein R is Amorphous silica. m. i

methyl, ie, the compound 5abromo-5 trifluommethyl-6- Asbestine Vmethoxyhydrouracil.

Spar varnish t c Linseed oil; Q bodied Mineral shits Water Co drier 1'6percent Pb drier (24 percent) Mndrier 6 (percent) Total weight v'QE'REIGN PATENTS 6404756 ll/1964- Netherlands" OTHER REFERENCES Johnsom78.: Chemical Abstracts, voli 2,. 279% 27.93 (1908 19 Yale, Harry it.Journal of Medicinal. and Pharmacetitical. Chemistry. vol L N '2,(1.950), pp 121-133,

O/W all-purpose cream Mineral oil means... .v

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